1. Field of Invention
The present invention relates to novel molecules inhibit proteins' function that may be for pharmaceutical applications. More particularly, the present invention relates to inhibitors of matrix metalloproteinase and tumor necrosis factor.
2. Description of Related Art
Matrix metalloproteinases (MMPs) constitute a family of at least 28 zinc containing proteolytic enzymes that play an integral role in the physiology of the extracellular matrix (ECM). MMPs play a major role in the degradation of the basement membrane and the remodeling of the ECM. Certain normal physiological processes such as fetal development, inflammatory cell migration, wound healing and angiogenesis depend on the controlled and concerted activity of the MMPs and the natural tissue inhibitors of metalloproteinases (TIMPs). In pathological processes, such as cancer, specific MMPs may be recruited to permit primary tumor growth and metastatic disease. Activation of these MMPs has been implicated in tissue invasiveness, metastases and angiogenesis. Thus, MMP inhibition offers a novel and possibly additive therapy to current treatment for many different types of cancer (Johnson, L. J., Dyer, R., and Hupe, D. J. Matrix Metalloproteinases. Current Opinion in Chemical Biology; 1998, 2: 466-471).
There are three distinct classes of MMPs by target: collagenases (MMP-1, MMP-8, and MMP-13), stromelysins (MMP-3, MMP-10, MMP-11), and gelatinases (MMP-2 and MMP-9). MMPs are secreted into the ECM in a proenzyme form, which requires activation by other enzymes. One class of activators is the enzyme membrane type MMP (MT-MMP). The MT-MMPs (MMP-14, MMP-15, MMP-16, MMP-17) have a transmembrane domain and are essential in activating pro-MMP.
Among the MMPs mentioned above, over-expression of certain MMPs (MMP-2 and MMP-9) have been implicate development and have been evaluated extensively in different tumors such colon, gastric, head and neck, prostate, and lung cancer. For example, studies shown that in colorectal cancer, both MMP-2 and MMP-9 (in both pro and active forms) are over-expressed in cancerous tissue when compared with the normal mucosa. Similar findings have been shown in gastric cancer and pancreatic cancer (Gress T. M., Muller-Pillasch F., Lerch, M. M., et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int. J. Cancer 1995, 62:407-413; Normura H, Sato H. Seiki M. et al. Expression of membrane type-matrix metalloproteinase in human gastric cancinomas. Cancer Res 1995; 55:3263-3266; Parsons S L, Watson S A, Brown P D, et al. Matrix metalloproteinases. Br. J. Surg. 1997, 87: 160-166). MMP-2 and MMP-9 over-expression also appear to correlate with tumor stage, tumor aggressiveness and poor prognosis for gastrointestinal, cervical, bladder and lung tumors (Nuovo G J, MacConnell P B, Simisir A, et al. Correlation of the in situ detection of polymerase chain reaction-amplified metalloproteinase complementary DNA and their inhibitors with prognosis in cervical carcinoma. (Cancer Res. 1995, 55:267-275; Davies B, Wasman J, Wasan H, et al.). Levels of matrix metalloproteinases in bladder cancer correlate with tumor grade and invasion. (Cancer Res. 1993, 53: 5365-5369; Brown P D, Bloxidge R E, Stuart N S, et al.). Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small cell lung carcinoma. (J. Natl. Cancer Inst. 1993, 85: 574-578). Although there is clear over-expression of MMP in certain tumors, there is variability of over-expression of MMP in different tumor types. For example, Fieberg, et al, studied expression patterns of MMP-2, MMP-3, and MMP-7 in 47 human tumor xenografts. Their results showed varying degrees of MMP-2 over-expression with 100% of soft tissue sarcomas, 84% of melanomas, 53% of testicular carcinoma and 26% of bladder cancers exhibiting MMP-2 over-expression (Fieberg H, Klostermeyer A, Schuler J B). Characterization of matrix metalloproteinases in 47 human tumor xenografts who high expression of MMP2 in melanomas and sarcomas (abstract no. 3058). Proceedings of the 90th Annual Meeting of the American Association for Cancer Research 1999 Apr. 10-13, Philadelphia (Pa.)). These results suggest that MMP-2 is a reasonable therapeutic target for these tumor types.
TNFα (tumor necrosis factor-α) plays an important role in the host defense. It causes resistance to many pathogenic microorganisms and some viruses as well. Even if TNFα has undoubtedly a beneficial function in activation of host defense, its uncontrolled production (mainly on the systematic level) can lead to pathological consequences. It plays significant role in the pathogenesis of septic shock, characterized among others by hypotension and multiple organ failure. It is the main mediator of cachexia characterized by abnormal weight-loss of cancer patients. Often it is detected in synovial fluid of patients suffering from arthritis. There is a broadening spectrum of disease, where it could play some roles. Compounds inhibiting the release of TNFα therefore may be used in the treatment of numerous pathologies in which TNFα is involved, such as rheumatoid arthritis, Crohn's disease, plaque sclerosis, septic shock, cancer or cachexia associated with an immunodeficiency, these examples not being restrictive.